Conventional cough preparations containing an effective anti-tussive agent such as codeine have long been used for the symptomatic relief of coughs. However, codeine has various side effects which are undesirable.
Accordingly, the present invention relates to compounds and pharmaceutical compositions having anti-tussive activity, and a method of treating warm-blooded animals affected by coughs by administering an effective amount of the compounds or the pharmaceutical compositions of the invention.
The problems of the prior art have been overcome by the present invention, which provides pharmaceutical compositions possessing anti-tussive activity, and a method of administering the same to warm-blooded animals, including humans. The active anti-tussive agent in accordance with the present invention is a novel quarternary ammonium compound represented by the following formula (I), or a solvate or pharmaceutically acceptable salt thereof: 
wherein Y and E are independently selected from xe2x80x94CH2xe2x80x94R16 or a group represented by the following formula (II): 
wherein R, R1, R2, R3, R4, R5, R6 and R16 are independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkoxyalkyl and C7-C11 aralkyl; m is an integer of from 1 to 8 and n is an integer of from 0 to 8; A is selected from C5-C12 alkyl, a C3-C13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X): 
where R7, R8, R9 R10, R11 and R12 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, C1-C6 thioalkyl, aryl and N(R13, R14) where R13 and R14 are independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6 alkyl, and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to X when Z is CH, or X may be a direct bond to Z when Z is N, or Z may be directly bonded to R15 when Z is N and X is not a direct bond to Z, R15 is selected from hydrogen, C1-C6 alkyl, C3-C8 cyclocalkyl, aryl and benzyl; and X is Nxe2x80x94Re except when Z in A is nitrogen and X is a direct bond to Z; An is the acid addition salt of a pharmaceutically acceptable acid or the anion from a pharmaceutically acceptable salt, and isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that Y and E cannot both be xe2x80x94CH2xe2x80x94R16 in the same compound[, and when Y is represented by formula (II) where n is 0, m is 1, R2 and R3 are each hydrogen, X is Nxe2x80x94H and A is represented by formula (III), then E is not xe2x80x94CH2xe2x80x94R16 or the same as Y].
Within the respiratory tract the epithelium of the larynx, trachea, and larger bronchi contains sensory nerves that are responsible for cough. Coughing is initiated when sensory receptors in the respiratory tract receive stimuli of sufficient intensity to evoke an increase in afferent nerve impulse activity. Cough reflexes can be provoked easily by mechanical and chemical stimuli applied to the epithelium of either the larynx or tracheobronchial tree. There are three main groups of airway sensory receptors which may be involved in the cough reflex initiated from these sites: the slowly adapting stretch receptors, the rapidly adapting (irritant) receptors (RARs), and the pulmonary and bronchial C-fibre receptors. Each is distributed throughout the tracheobronchial tree and the last group is also present in the alveolar wall. Irritant and C-fibre receptors have also been identified in the larynx. Stimulation of irritant receptors evokes the cough reflex; stimulation of the C-fibre receptors may either evoke or inhibit the cough reflex; stimulation of the slowly adapting stretch receptors may facilitate the cough reflex.
Drugs which inhibit cough may act at a variety of sites, both peripherally and centrally. For example, it is generally assumed that the anti-tussive efects of currently available opiates are mediated centrally through an action on the xe2x80x98cough centrexe2x80x99 in the medulla (D. T. Chou et al. J. Pharmacol. Exp. Ther. 1975, 194, 499). Thus the number of potential sites of action of anti-tussive drugs includes all components of the cough reflex pathway, from its initiation to its final synchronized motor response.
It has now been discovered that a class of cation channel modulator/blockers are of potential use in the treatment and/or prevention of cough in warm-blooded animals including humans. The cation channel modulator/blockers of the present invention inhibit the initiation of an action potential by a cation channel at the peripheral fine afferent nerve ending or on peripheral sensory neuron that is responsible for inducing cough or triggering cough reflex. The cation channel at peripheral fine afferent nerve ending or on peripheral sensory neuron may be coupled as the transduction mechanism to one or more sensory receptors described above (RARs, C-fibre receptors and the slowly adapting stretch receptors).
The cation channel at the peripheral fine afferent nerve ending or peripheral sensory neuron is identified to be a member of the acid-sensing ion channels (ASIC) or the dorsal root acid-sensing ion channel (DRASIC). (see e.g. R. Waldmann et al. Curr. Opin. Neurobiol. 1998, 8(3), 418).
In another embodiment, the present invention provides the cation channel modulator/blockers that are quaternary ammonium compounds.
In another embodiment, the present invention provides the cation channel modulator/blockers that are quaternary ammonium compounds of formula I.
In another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel, or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel that is at the peripheral fine afferent nerve ending or on a peripheral sensory neuron of said warm-blooded animal, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel that is at the peripheral fine afferent nerve ending or on a peripheral sensory neuron which may be coupled as the transduction mechanism to one or more sensory receptors of said warm-blooded animal, or a pharmaceutically acceptable salt thereof.
In still another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel that inhibits initiation of an action potential at the peripheral fine afferent nerve ending or on a peripheral sensory neuron of said warm-blooded animal, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel that inhibits initiation of an action potential at the peripheral fine afferent nerve ending or on a peripheral sensory neuron that is responsible for inducing cough or triggering cough reflex of said warm-blooded animal, or a pharmaceutically acceptable salt thereof.
In still another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a cation channel that inhibits from extracellular loci the initiation of an action potential at the peripheral fine afferent nerve ending or on a peripheral sensory neuron that is responsible for inducing cough or triggering cough reflex of said warm-blooded animal, or a pharmaceutically acceptable salt thereof.
In still another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of an acid-sensing ion channel (ASIC), or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of a dorsal root acid-sensing ion channel (DRASIC), or a pharmaceutically acceptable salt thereof.
In still another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of an acid-sensing ion channel (ASIC) at the peripheral fine afferent nerve ending or on a peripheral sensory neuron, or a pharmaceutically acceptable salt thereof.
In still another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a modulator/blocker of an acid-sensing ion channel (ASIC) at the peripheral fine afferent nerve ending or on a peripheral sensory neuron which may be coupled as the transduction mechanism to one or more sensory receptors, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a quaternary ammonium compound functioning as a modulator/blocker of an acid-sensing ion channel (ASIC) at the peripheral fine afferent nerve ending or on a peripheral sensory neuron, or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a method for the treatment and/or prevention of cough in warm-blooded animals including human, which comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of an antitussive comprising as the antitussive effective ingredient a quaternary ammonium compound of Formula (I) functioning as a modulator/blocker of an acid-sensing ion channel (ASIC) at the peripheral fine afferent nerve ending or on a peripheral sensory neuron, or a pharmaceutically acceptable salt thereof.